Pain is a major clinical problem and its alleviation by any method is beneficial to patients and society. The sensation of pain is usually initiated by the activation of peripheral sensory neurons, called nociceptors. Chemical stimuli may sensitize nociceptors resulting in allodynia and/or hyperalgesia whereas their desensitization will result in hypoalgesia or a diminution of pain. Topical applications of capsaicin, the pungent compound in hot pepper, is used clinically to reduce pain arising from arthritis, oral facial pain, and even chronic pain. The mechanism by which pro-inflammatory mediators can sensitize nociceptors is relatively well known. What is not known, and which is the primary topic of this proposal, is how pungent vanilloid receptor activators like capsaicin and its non-pungent analogue, olvanil, can selectively desensitize (or anesthetize) nociceptors in mammalian trigeminal neurons. The interactions between vanilloid receptors and voltage-gated ion channels that cause desensitization in nociceptors are not understood. The mechanisms by which olvanil can depolarize nociceptors without causing excitation is also unknown and is obviously important in developing novel types of anesthetics. Olvanil also activates cannabinoid CB1 receptors, so the endogenous pathways that lead nociceptor desensitization via the dual activation of vanilloid and CB1 receptors will be determined by investigating their effects on voltage-gated sodium (VGSC) and potassium (VGPC) channels. These experiments will determine whether only neurons having vanilloid and or CB1 receptors will be desensitized by capsaicin or olvanil and the intracellular pathways that modulate VGSCs (TTX-s, TTX-r) and VGPCs (IK and IA). Electrophysiological measurements quantifying the efficacy of capsaicin and olvanil to inhibit VGSC and VGPCs will be combined with single cell RT-PCR of the various subunits of VGSC and VGPCs, with IB4 labeling, and with enzyme immunoassay measurements. This information will lead to novel anesthetic mechanisms that involve the reversible desensitization of nociceptors.